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Review
Pulmonary Hypertension Associated with Connective Tissue Disease Srinivas Rajagopala, Molly Mary Thabah1 Department of Pulmonary Medicine, PSG Institute of Medical Sciences and Research, Coimbatore, Tamil Nadu, 1Department of Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India Received: June, 2016 Accepted: October, 2016 Published: February, 2017
Address for correspondence: Dr. Molly Mary Thabah, Department of Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, Dhanvantri Nagar, Puducherry ‑ 605 006, India. E‑mail:
[email protected]
Abstract Pulmonary hypertension (PH) is an important cause of morbidity and mortality in connective tissue diseases (CTDs). CTDs may cause PH due to several mechanisms; pulmonary arterial hypertension, associated interstitial lung disease, neuromuscular disease, and/or sleep disordered breathing leading to hypoxia, associated thromboembolic PH, and pulmonary venous hypertension due to left ventricular dysfunction. PH can be measured on echocardiography, but the gold standard for diagnosis is right heart catheterization. PH‑specific therapy in addition to immunosuppression is the most common treatment used though data are scant. In this narrative review, we discuss the epidemiologic burden, clinical presentation, evaluation, and management of PH in CTDs. Key Words: Connective tissue disease, mixed connective tissue disease, progressive systemic sclerosis, pulmonary hypertension, systemic lupus erythrematosus
Introduction Pulmonary hypertension (PH) is defined by a resting mean pulmonary arterial pressure (mPAP) of ≥25 mm Hg as measured by right heart catheterization (RHC).[1] Pulmonary arterial hypertension (PAH) is a subgroup of PH characterized by precapillary PH, as defined by a pulmonary capillary wedge pressure 3 Wood Units, in the absence of other causes of precapillary PH such as lung diseases, chronic thromboembolic PH (CTEPH), or other rare diseases. A wide variety of diseases cause PH [Table 1]; the current classification approaches this from the etio‑physiological basis for elevated pulmonary pressures.[2] The right‑sided system is a low‑pressure system; normal pulmonary arterial systolic pressures (PASP) ranges from 15 to 30 mm Hg, diastolic pressures from 4 to 12 mm Hg and normal mPAP is ≤20 mm Hg. mPAP values between 21 and 24 mm Hg are elevated, but are of uncertain clinical significance.[1] Irrespective of cause, chronic elevation of pulmonary arterial pressures (PAPs) ≥25 mm Hg leads to right ventricular (RV) strain, dilatation, dysfunction, and failure.[3] Connective tissue diseases (CTDs) are the second most common cause of PAH, after idiopathic PAH (iPAH).[4,5] CTDs may cause PH Access this article online Website: www.indianjrheumatol.com
DOI: 10.4103/0973-3698.199124
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due to several mechanisms; PAH (Group 1), PH associated with CTD‑interstitial lung disease (ILD), neuromuscular disease and/or sleep disordered breathing leading to hypoxia (often secondary to steroid therapy for CTD and weight gain, Group 3), associated CTEPH (Group 4) and pulmonary venous hypertension due to left ventricular dysfunction secondary to cardiomyopathy or accelerated atherosclerosis (systolic or diastolic, Group 2).[6] Pulmonary venoocclusive disease (PVOD) may also be associated with CTD (especially systemic sclerosis [SSc]) and lead to development of PAH.[7] Elucidation of the mechanism in an individual has crucial management and prognostic implications as discussed below. This narrative will discuss the epidemiologic burden, pathophysiology, and evaluation and management of patients with CTD‑PAH.
Prevalence of Pulmonary Hypertension in Connective Tissue Diseases and Limitations in Available Data There are no community‑based prevalence studies about CTD as a cause of PH. Most of our understanding of disease prevalence is from registry‑based studies of RHC‑confirmed PH that have their own biases. Comparing worldwide rates of CTDs as a cause of PH is further complicated This is an open access article distributed under the terms of the Creative Commons Attribution‑NonCommercial‑ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non‑commercially, as long as the author is credited and the new creations are licensed under the identical terms. For reprints contact:
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How to cite this article: Rajagopala S, Thabah MM. Pulmonary hypertension associated with connective tissue disease. Indian J Rheumatol 2017;12:38-47.
© 2017 Indian Journal of Rheumatology | Published by Wolters Kluwer - Medknow
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Table 1: World Health Organization classification of pulmonary hypertension[1,2] Category 1 1.1 1.2
Etiology PAH Idiopathic Familial BMPR2 mutations associated Others‑ALK‑1, ENG, SMAD9, CAV1, KCNK3 1.3 Drug‑ and toxin related‑appetite suppressants (e.g., aminorex, fenfluramine, dexfenfluramine, and diethylpropion), toxic rapeseed oil, and benfluorex 1.4 Associated with 1.4.1 CTD 1.4.2 HIV‑associated 1.4.3 Porto PH 1.4.4 Congenital heart disease (left to right shunts) 1.4.5 Schistosomiasis 1’ Pulmonary veno‑occlusive disease and/or pulmonary capillary hemangiomatosis Idiopathic Inherited: EIF2AK4 mutations, others Drug‑ and toxin‑related Associated with CTD, HIV 1” PPHN 2 PH owing to left heart disease (pulmonary venous hypertension) 2.1 Left ventricular systolic dysfunction 2.2 Left ventricular diastolic dysfunction 2.3 Valvular disease 2.4 Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies 3 PH owing to lung disease and/or hypoxia 3.1 Chronic obstructive pulmonary disease 3.2 Interstitial lung disease 3.3 Other pulmonary diseases with mixed restrictive and obstructive patterns 3.4 Sleep‑disordered breathing 3.5 Alveolar hypoventilation disorders 3.6 Chronic exposure to high altitude 3.7 Developmental lung diseases 4 CTEPH and other obstructions Obstructions: Angiosarcoma, intravascular tumors, arteritis, congenital venous stenosis 5 PH with unclear multifactorial mechanisms 5.1 Hematologic disorders: Chronic hemolytic anemia, myeloproliferative disorders, splenectomy 5.2 Systemic disorders: Sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis 5.3 Metabolic disorders: Glycogen storage disorders, gaucher disease, thyroid disorders 5.4 Others: Tumoral micronagiopathy, fibrosing mediastinitis, chronic renal failure, segmental PH Reproduced with permission of the European Society of Cardiology and European Respiratory Society©. Eur Respir J 2015;46:903‑75. ALK‑1: Activin‑like receptor kinase‑1, ENG: Endoglin, SMAD9: Mothers against decapentaplegic 9, CAV1: Caveolin‑1, KCNK3: Potassium channel superfamily member‑3. PAH: Pulmonary arterial hypertension, BMPR2: Bone morphogenetic protein receptor 2, CTD: Connective tissue disease, HIV: Human immunodeficiency virus, PPHN: Persistent pulmonary hypertension of the newborn, CTEPH: Chronic thromboembolic pulmonary hypertension, PH: Pulmonary hypertension
by the inadequacy of RHC data and reporting of echocardiography‑based PH diagnosis alone. Although PH can be measured on echocardiography, the gold standard for diagnosis is RHC. There are several problems with the use of echocardiography as the sole diagnostic modality for PH. Echocardiography uses Doppler ultrasound to estimate pulmonary artery pressure. The maximum tricuspid regurgitant (TR) jet is recorded and PASP is calculated 39
using formula PASP = (4 × [TRV]2 + RAP), where RAP is right atrial pressure, TRV is TR velocity measured in m/s. PH is likely if PASP is >50 mm Hg and TRV is >3.4 and unlikely if TRV is ≤2.8. However, as noted above, the diagnosis of PH needs direct measurement of PAP by RHC. Correlation coefficient of PASP between echocardiography and RHC is high at 0.84 for left heart disease, but is much lower (0.58) for right heart disease. Moreover, the difference Indian Journal of Rheumatology ¦ Volume 12 ¦ Issue 1 ¦ March 2017
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between the echocardiography and RHC pressures differs by ≥10 mm Hg in 37.6%.[8] Recent data, however, suggests excellent correlation between PH by RHC and RVSP by echocardiography when TR signal is interpretable (area under the curve 0.97 for RVSP and 0.98 for RVSP and eccentricity index (P > 0.05).[9] Tricuspid regurgitation jet, needed to quantify PASP, however, may be absent in up to 20%–39% of patients. In clinical practice, RHC is often restricted to patients with an intermediate probability of moderate PAH, when performed. In registries, CTD as a cause of PAH ranges from 15% to 30%, with SSc accounting for 62%–94% of the patients with CT‑PAH Table 2.[10] In Asian populations, systemic lupus erythrematosus (SLE) has been reported to cause a higher proportion of up to 35%–49% of patients with PH, possibly reflecting the higher prevalence of SLE in this population Table 2.[11,12]
the above.[13] Exercise‑induced PH has also been recognized as a risk factor, with 20% developing overt PH later. The Cochin index utilizing age, FVC, and DLco/VA has been proposed for prediction of PH in SSc; however, only 17% in the highest quartile have PH and it has not been externally validated yet.[16]
Pulmonary Hypertension in Systemic Sclerosis
PH is rare in patients with rheumatoid arthritis. Cohort studies have reported a prevalence of 20%–26.7% based on PASP >30 mm Hg; however only 4% (2/50) had values ≥40 mm Hg that are likely to be associated with mPAP ≥25 mm Hg in RHC.[17] Similar data about prevalence is available from smaller cohorts of patients with dermatomyositis and primary Sjogren’s syndrome Table 2.
Pulmonary complications are the leading cause of death in SSc.[13] This includes the development of ILD, PH or both. Precapillary PH prevalence ranges from 5% to 15% (15% rule) Table 2.[10] In the DETECT study [Figure 1] that enrolled patients with SSc and risk factors for PH (SSc for >3 years and a diffusing capacity of the lung for carbon monoxide (DLCO) 40 mm Hg 24% Similar prevalence of PH in limited versus diffuse SSc (26% vs. 22%, P=0.9) Ware et al.[22] 2015 SLE 50 TTE; PASP >25 mm Hg 11/23 (45%) aPL+SLE Only 7/23 (30.4%) had PASP >40 mm Hg patients had PH versus and only 4/7 had CTPA performed to 2/27 (7.5%) aPL− rule out CTEPH [23] Kommireddy et al. 2015 SLE‑PAH 24 TTE; PASP >30 mm Hg 24 consecutive SLE‑PH No data on prevalence patients *Rheumatoid arthritis (119), SLE (n=32), SSc (n=13), polymyositis (n=11), pSS (n=10), MCTD (n=5), Ankylosing spondylitis (n=5). PH: Pulmonary hypertension, CTD: Connective tissue disease. TTE: Transthoracic echocardiography, MCTD: Mixed connective tissue disease, SSc: Systemic sclerosis, SLE: Systemic lupus erythematosus, aPL: Antiphospholipid antibodies, 2D echo: Two‑dimensional echocardiography, CTEPH: Chronic thromboembolic pulmonary hypertension, PASP: Pulmonary artery systolic pressure, PAH: Pulmonary arterial hypertension, CTPA: Computed tomographic pulmonary angiography
search terms “PAH” or “PH” and India. In addition, we also performed three other searches using the terms SSc and India; MCTD and India; SLE and India. This was supplemented by a search in IndMed and the Internet search engine Google using the terms “PAH” or “PH.” The search returned 1675 articles. Abstracts and full texts, where available, were retrieved and data abstracted in a predetermined proforma for information about PH in CTDs in India. Case reports, reviews and observational studies about CTDs cohorts in general were not included. Our search retrieved five studies (two each for SSc and SLE and one for MCTD).[18‑23] There were no articles related to Sjogren’s or rheumatoid arthritis. Data from the individual studies on the prevalence of PH in CTDs from India and their limitations are summarized in Table 3.
Pathophysiology Development of PAH is likely a multi‑hit process, with pulmonary endothelial injury and immune dysregulation being key events. The initiating event and subsequent pathway for development of PH in most patients remains unclear. Intact bone morphogenetic protein receptor (BMPR2)‑signaling pathway is needed for normal lung vascular wound healing. However, few patients with sporadic iPAH or CTD‑PAH have BMPR2 mutations and
